This proposal is to request support for a Keystone Symposia meeting entitled New Directions in Small Molecule Drug Discovery, organized by William J. Greenlee, George Hartman and Anna K. Mapp, which will be held in British Columbia, Canada from April 20 - 25, 2010. The purpose of this meeting is to highlight exciting new opportunities in the discovery of small molecule drug candidates, including the following: 1. Novel targets for small molecules, including disruption of protein-protein interactions, allosteric modulation of receptors and enzymes, and direct interactions with transcription factors. 2. Enabling technologies for the discovery of new small molecule leads, including diversity-oriented screening, fragment screening, and affinity screening. 3. the most successful structure-based design approaches to the optimization of leads. A focus of the conference will be successful applications structure-based design in the discovery of therapeutics for the treatment of HCV infection (protease inhibitors) and cancer (protein kinase inhibitors). A session comprising first-time disclosures of Phase 2 clinical candidates will illustrate successful applications of structure-based design in drug discovery. Opportunities for interdisciplinary interactions will be significantly enhanced by the concurrent meeting on Computer-Aided Drug Design, which will share four sessions and a keynote with this meeting. PUBLIC HEALTH RELEVANCE: Successful discovery of small molecule drug candidates has led to new and exciting medicines that address major medical needs. The increasing expense and risk in small molecule drug discovery has highlighted the need for new approaches and technologies that can improve the success rate of drug candidates and reduce their attrition in development. This first Keystone Symposia meeting on New Directions in Small Molecule Drug Discovery will focus on new approaches and enabling technologies that will contribute to the identification of successful small molecule drug candidates.